N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer’s Disease

The discussion of whether amyloid plaque Aβ is a valid drug target to fight Alzheimer’s disease (AD) has been a matter of scientific dispute for decades. This question can only be settled by successful clinical trials and the approval of disease-modifying drugs. However, many clinical trials with antibodies against different regions of the amyloid Aβ peptide have been discontinued, as they did not meet the clinical endpoints required. Recently, passive immunization of AD patients with Donanemab, an antibody directed against the N-terminus of pyroglutamate Aβ, showed beneficial effects in a phase II trial, supporting the concept that N-truncated Aβ is a relevant target for AD therapy. There is long-standing evidence that N-truncated Aβ variants are the main variants found in amyloid plaques besides full-length Aβ1–42, t, therefore their role in triggering AD pathology and as targets for drug development are of interest. While the contribution of pyroglutamate Aβ3–42 to AD pathology has been well studied in the past, the potential role of Aβ4–42 has been largely neglected. The present review will therefore focus on Aβ4–42 as a possible drug target based on human and mouse pathology, in vitro and in vivo toxicity, and anti-Aβ4-X therapeutic effects in preclinical models.

An overview of glutaminyl cyclase inhibitors for Alzheimer’s disease

A diverse range of N-terminally truncated and modified forms of amyloid-β (Aβ) oligomers have been discovered in Alzheimer’s disease brains, including the pyroglutamate-Aβ (AβpE3). AβpE3 species are shown to be more neurotoxic when compared with the full-length Aβ peptide. Findings visibly suggest that glutaminyl cyclase (QC) catalyzed the generation of cerebral AβpE3, and therapeutic effects are achieved by reducing its activity. In recent years, efforts to effectively develop QC inhibitors have been pursued worldwide. The inhibitory activity of current QC inhibitors is mainly triggered by zinc-binding groups that coordinate Zn2+ ion in the active site and other common features. Herein, we summarized the current state of discovery and evolution of QC inhibitors as a potential Alzheimer’s disease-modifying strategy.

A modification-specific peptide-based immunization approach using CRM197 carrier protein: Development of a selective vaccine against pyroglutamate Aβ peptides

ABSTRACTStrategies aimed at reducing cerebral accumulation of the amyloid-β (Aβ) peptides have therapeutic potential in Alzheimer’s disease (AD). Aβ immunization has proven to be effective at promoting Aβ clearance in animal models but adverse effects have hampered its clinical evaluation. The first anti-Aβ immunization clinical trial, which assessed a full-length Aβ1-42 vaccine, increased the risk of encephalitis most likely because of autoimmune pro-inflammatory T helper 1 (Th1) response against all forms of Aβ. Immunization against less abundant but potentially more pathologically relevant Aβ products, such as N-terminally-truncated pyroglutamate-3 Aβ (AβpE3), could provide efficacy and improve tolerability in Aβ immunotherapy. Here, we describe a selective vaccine against AβpE3 using the diphtheria toxin mutant CRM197 as carrier protein for epitope presentation. CRM197 is currently used in licensed vaccines and has demonstrated excellent immunogenicity and safety in humans. In mice, our AβpE3:CRM197 vaccine triggered the production of specific anti-AβpE3 antibodies that did not cross-react with Aβ1-42, non-cyclized AβE3, or N-terminally-truncated pyroglutamate-11 Aβ (AβpE11). AβpE3:CRM197 antiserum strongly labeled AβpE3 in insoluble protein extracts and decorated cortical amyloid plaques in human AD brains. Anti-AβpE3 antibodies were almost exclusively of the IgG1 isotype, suggesting an anti-inflammatory Th2 response bias to the AβpE3:CRM197 vaccine. To the best of our knowledge, this study shows for the first time that CRM197 has potential as a safe and suitable vaccine carrier for active and selective immunization against specific protein sequence modifications or conformations, such as AβpE3.